Identification of CaVβ1 isoforms required for neuromuscular junction formation and maintenance

Vergnol, A.; Bourguiba, A.; Bauche, S.; Traore, M.; Gelin, M.; Gentil, C.; Pezet, S.; Saillard, L.; Meunier, P.; Lemaitre, M.; Perronnet, J.; Tores, F.; Gautier, C.; Guesmia, Z.; Allemand, E.; Batsche, E.; Pietri-Rouxel, F.; Falcone, S.

doi:10.1101/2025.06.10.658789

bioRxiv · 10.1101/2025.06.10.658789

Identification of CaVβ1 isoforms required for neuromuscular junction formation and maintenance

Vergnol, A.·Bourguiba, A.·Bauche, S.·Traore, M.·Gelin, M.·Gentil, C.·Pezet, S.·Saillard, L.·Meunier, P.·Lemaitre, M.·Perronnet, J.·Tores, F.·Gautier, C.·Guesmia, Z.·Allemand, E.·Batsche, E.·Pietri-Rouxel, F.·Falcone, S.

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Abstract

Voltage-gated Ca{superscript 2} channels (VGCCs) are regulated by four CaV{beta} subunits (CaV{beta}1-CaV{beta}4), each showing specific expression patterns in excitable cells. While primarily known for regulating VGCC function, CaV{beta} proteins also have channel-independent roles, including gene expression modulation. Among these, CaV{beta}1 is expressed in skeletal muscle as multiple isoforms. The adult isoform, CaV{beta}1D, localizes at the triad and modulates CaV1 activity during Excitation-Contraction Coupling (ECC). In this study, we investigated the lesser-known embryonic/perinatal CaV{beta}1 isoforms and their roles in neuromuscular junction (NMJ) formation, maturation, and maintenance. We found that CaV{beta}1 isoform expression is developmentally regulated through differential promoter activation. Specifically, CaV{beta}1A is expressed in embryonic muscle and reactivated in denervated adult muscle, alongside the known CaV{beta}1E isoform. Nerve injury in adult muscle triggers a shift in promoter usage, resulting in re-expression of embryonic/perinatal Cacnb1A and Cacnb1E transcripts. Functional analyses using aneural agrin-induced AChR clustering on primary myotubes demonstrated that these isoforms contribute to NMJ formation. Additionally, their expression during early postnatal development is essential for NMJ maturation and long-term maintenance. These findings reveal previously unrecognized roles of CaV{beta}1 isoforms beyond VGCC regulation, highlighting their significance in neuromuscular system development and homeostasis.

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Vergnol, A., Bourguiba, A., Bauche, S., Traore, M., Gelin, M., Gentil, C., Pezet, S., Saillard, L., Meunier, P., Lemaitre, M., Perronnet, J., Tores, F., Gautier, C., Guesmia, Z., Allemand, E., Batsche, E., Pietri-Rouxel, F., Falcone, S.. 2025-06-15. Identification of CaVβ1 isoforms required for neuromuscular junction formation and maintenance. https://doi.org/10.1101/2025.06.10.658789

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